NEWTON, Mass.—Siamab Therapeutics continues exploring the efficacy of its Sialyl-Tn antibody-drug conjugate to combat ovarian cancer, with more positive preclinical data being reported in the peer-reviewed PLOS ONE journal in late July. The data published online indicate that humanized Sialyl-Tn successfully impeded the expression of ST1 and inhibited tumor growth in multiple ovarian cancer models in mice. These data were accompanied by positive results from an initial toxicity study in nonhuman primates that showed no areas of concern for the treatment.
The data validate Siamab’s work with novel glycan-targeting cancer antibodies. Glycans are carbohydrates ubiquitous in human cells which can mutate and become abnormal. Once mutated, they become highly cancer-specific, tumor-associated carbohydrate antigens (TACAs), and are found in the majority of solid tumors including ovarian, pancreatic, prostate, colon, gastric and breast cancers. Tumor cells focus on TACAs, allowing the suppression of immune function, the facilitation of metastasis into healthy tissue and the ability to withstand chemotherapy. Siamab, among other biopharmaceutical companies, believes that therapeutic antibodies targeting TACAs have the potential to not only kill cancer cells but also re-engage the immune system and overcome chemoresistance.
According to Jeff Behrens, president and CEO of Siamab, “ST1 targets the Sialyl Tn antigen (known also as STn). STn is a ‘TACA,’ a tumor-associated carbohydrate antigen that has been known to be present on several solid tumors, including ovarian, for a number of years. Although a known target of interest, it is quite difficult to discover and engineer antibodies that bind to TACAs with high specificity and affinity and are therefore suitable for pharmaceutical use. Siamab’s core competency is discovering such antibodies—high-specificity and -affinity anti-TACA monoclonal antibodies (mAbs). We use a technology developed in collaboration with Dr. Ajit Varki’s lab at University of California, San Diego, a glycan microarray, that makes this possible.”
STn is a carbohydrate antigen discovered as a cancer marker in the early 1980s. It has been studied in a variety of contexts as a target for interventions meant to slow or stop cancer. The STn target is highly expressed in several solid tumors, and the humanized ST1 antibody-drug conjugate (ADC) demonstrated in-vitro cytotoxicity specific to STn-expressing ovarian cancer cell lines and inhibited tumor growth in-vivo in both cell line and PDX ovarian cancer mouse models. The study did not find any other adverse reactions in the testing, suggesting a high tolerance for specifically targeting STn. The paper also reported that the humanized anti-STn ADC, when tested in nonhuman primates, showed no toxicity, even when administered at 12 times the therapeutic dose.
Dr. Bo Rueda, the director of The Vincent Center for Reproductive Biology at Massachusetts General Hospital and the principal investigator of studies described in the paper, said, “This new paper includes important recent murine patient-derived xenograft (PDX) findings that show that the compound is both effective in multiple PDX models and well tolerated with no target-related toxicities. The known specificity of STn for malignant tissue in combination with the high affinity and STn-specific selectivity of the humanized ST1 antibody therapeutic provide a compelling rationale to evaluate ST1-ADC in patients with STn-expressing ovarian tumors.”
Siamab now has what they believe to be a compelling preclinical data package on the ST1 program that supports bringing the program into human clinical trials in ovarian cancer, and are hoping to announce funding plans to initiate Phase 1 trials later this year. Ovarian cancer is an excellent first treatment target, but there is also high STn expression in pancreatic, prostate, gastric and colon cancer. In addition to a treatment protocol, Siamab is hopeful that their ST1 ADC may also serve as a diagnostic tool.
“We have been working with Dr. Rueda to explore the potential to use our mAbs as diagnostics for ovarian cancer. Current ovarian cancer diagnostics, including the standard of care CA125 test, are not specific and sensitive enough to be used as screening tools. Along with Dr. Rueda, we are making excellent progress on this goal and hope to be able to publish data later this year,” asserts Behrens.
There is an urgent need for better means to detect ovarian cancer earlier, and for a more effective treatment for later stages of the disease. An estimated one in 75 women will develop ovarian cancer during her lifetime. The American Cancer Society estimates that there will be over 22,280 new cases of ovarian cancer diagnosed in 2018, and that more than 14,240 women will die from ovarian cancer this year. Due to ovarian cancer’s non-specific symptoms and lack of early detection tests, only about 20 percent of all cases are found in stage I or II, when it can be more easily treated. If caught in stage III or higher, the survival rate can be as low as 28 percent.